Incidence of herpes simplex virus type 2 positivity among women living with human immunodeficiency virus in South Africa.

BACKGROUND: For women living with HIV (WLHIV), co-infection with herpes simplex virus type 2 (HSV-2) causes severe genital ulcers and presents additional challenges for their HIV care. To inform preventive strategies, we aimed to determine the incidence and risk factors of HSV-2 positivity in a prospective cohort of South African women. METHODS: The CAPRISA 002 study enrolled women at acute HIV infection between 2004 and 2020. HSV-2 testing was conducted by multiplex polymerase chain reaction (PCR) assay on collected vaginal swabs up to twice annually during follow-up. We calculated incidence as the number of new cases per 100 person-years (PYs) and used Cox-proportional-hazard regression to identify factors associated with time-to-HSV-2 PCR positivity. RESULTS: At enrolment, the median age of 171 women was 24 years, interquartile range (IQR 21-28), and the estimated median days since HIV infection was 42 (IQR 22-65). Of participants tested at enrolment, HSV-2 antibody prevalence was 81.4% (105/129), and 10.6% (12/113) were positive by PCR. Among 147 women with a prior negative HSV-2 PCR diagnosis, we observed 47 new HSV-2 PCR positive cases over 424.4 PYs of follow-up, yielding an incidence rate of 11.1 cases per-100-PYs. HSV-2 PCR positivity incidence was higher among younger women (<25 years: adjusted Hazard Ratio [aHR] = 5.91, 95%CI 3.02-11.6), those with bacterial vaginosis (BV) (Nugent score 7-10: aHR = 2.17, 95%CI 1.15-4.10) and lower CD4 counts (<500 cells/µl: aHR = 2.04, 95%CI 1.08-3.87). CONCLUSION: After acute HIV infection in women, the incidence of HSV-2 PCR positivity was associated with younger age, BV diagnosis and lower CD4 count.

High-risk human papillomavirus prevalence among South African women diagnosed with other STIs and BV.

INTRODUCTION: Human papillomavirus (HPV) infection is a leading cause of cervical cancer. Although this relies on infection and persistence of HPV in epithelial cells, often occurring in the context of other sexually transmitted infections (STIs) and bacterial vaginosis (BV), data on the relationships between these and their relative effects on epithelial barrier integrity in women remain sparse. This study describes the epidemiology of HPV combined with STI and/or BV prevalence and the relative impact on matrix metalloproteinases (MMPs) among South African women. METHODS: Roche Linear Array was used for HPV genotyping in menstrual cup pellets of 243 HIV-negative women participating in the CAPRISA 083 cohort study. Vulvovaginal swabs were tested for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis using Xpert® CT/NG assay and lateral flow assay, and Gram staining was performed to diagnose BV using Nugent scoring criteria. Concentrations of 5 MMPs were measured in menstrual cup supernatants by multiplexed ELISA. Fisher's exact tests, Mann-Whitney U tests, and multivariable regression models determined associations between HPV infection, STI and/or BV, and MMP concentrations. RESULTS: HPV was prevalent in 34% of women (83/243; median 23 years, interquartile range (IQR) 21-27 years). Low-risk (lr) (71%, 59/83) and high-risk (hr)-HPV infections (54.2%, 45/83) were common. Hr-HPV was frequently detected in STI and/or BV-positive women compared to women without STIs or BV (p = 0.029). In multivariable analysis, BV was associated with increased odds of hr-HPV detection (OR: 2.64, 95%CI: 1.02-6.87, p = 0.046). Furthermore, Gardasil®9 vaccine-type strains were more frequently detected in women diagnosed with STI and/or BV (55.2%, 32/58 vs 24%, 6/25; p = 0.009). Among STI and/or BV-positive women, HPV detection was significantly associated with increased MMP-10 concentrations (b = 0.55, 95% CI 0.79-1.01; p = 0.022). CONCLUSION: Most women with hr-HPV had another STI and/or BV, emphasizing an urgent need for STI and BV screening and intensive scale-up of cervical cancer screening and HPV vaccination programmes. Furthermore, the study highlights the need for more extensive research to confirm and understand the relationship between HPV infection and barrier integrity.

Metronidazole Treatment Failure and Persistent BV Lead to Increased Frequencies of Activated T- and Dendritic-Cell Subsets.

Metronidazole (MDZ) treatment failure and bacterial vaginosis (BV) recurrence rates are high among African women. This cohort study identified genital immune parameters associated with treatment response by comparing vaginal microbiota and immune cell frequencies in endocervical cytobrushes obtained from 32 South African women with symptomatic BV pre- and post-metronidazole treatment. Cervical T- and dendritic-cell subsets were phenotyped using multiparameter flow cytometry and the composition of vaginal microbial communities was characterized using 16S rRNA gene sequencing. MDZ treatment led to a modest decrease in the relative abundance of BV-associated bacteria, but colonization with Lactobacillus species (other than L. iners) was rare. At 6 and 12 weeks, MDZ-treated women had a significant increase in the frequencies of CCR5+ CD4+ T cells and plasmacytoid dendritic cells compared to the pre-treatment timepoint. In addition, MDZ non-responders had significantly higher frequencies of activated CD4 T cells and monocytes compared to MDZ responders. We conclude that MDZ treatment failure was characterized by an increased expression of activated T- and dendritic-cell subsets that may enhance HIV susceptibility. These data suggest the need to further assess the long-term impact of MDZ treatment on mucosal immune response and the vaginal microbiota.

Incidence, recurrence, and prevalence of bacterial vaginosis from acute to chronic HIV infection in a prospective cohort of women in South Africa.

PURPOSE: We investigated the incidence, recurrence, prevalence, and risk factors for bacterial vaginosis (BV) diagnosis starting from acute HIV infection among South African women. METHODS: The Centre for the AIDS Programme of Research in South Africa 002 study tested and treated women for BV (Nugent score 7-10) once/twice annually from acute to chronic HIV infection (2004-2020). We estimated BV incidence as the number of new cases and recurrence as the number of subsequent diagnoses per 100 person-years (PYs). We fitted Anderson-Gil Cox-proportional-hazard regression models to determine factors associated with BV incidence or recurrence. RESULTS: Of 235 participants, the median age at enrollment was 25 years (Inter Quartile Range [IQR] 22-29). BV prevalence at enrollment was 50.6%. BV incidence was 23.9 cases per 100 PYs, and recurrence was 51.3 cases per 100 PYs. BV incidence/recurrence was associated with younger age (<25 years: adjusted hazard ratio [aHR] 1.70, 95% confidence interval [CI] 1.27-2.27), detectable HIV viral load (aHR 1.54, 95% CI 1.27-1.87) and lower CD4 count (<350 cells/µL: aHR 1.33, 95% CI 1.01-1.76). CONCLUSIONS: Our findings underscore the need for early antiretroviral treatment initiation with diagnostic BV and sexually transmitted infection care, especially among younger women.

Impact of Point-of-Care Testing on the Management of Sexually Transmitted Infections in South Africa: Evidence from the HVTN702 Human Immunodeficiency Virus Vaccine Trial.

BACKGROUND: Alternative approaches to syndromic management are needed to reduce rates of sexually transmitted infections (STIs) in resource-limited settings. We investigated the impact of point-of-care (POC) versus central laboratory-based testing on STI treatment initiation and STI adverse event (STI-AE) reporting. METHODS: We used Kaplan-Meier and Cox regression models to compare times to treatment initiation and STI-AE reporting among HVTN702 trial participants in South Africa. Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) were diagnosed POC at eThekwini clinic and in a central laboratory at Verulam/Isipingo clinics. All clinics used POC assays for Trichomonas vaginalis (TV) testing. RESULTS: Among 959 women (median age, 23 [interquartile range, 21-26] years), median days (95% confidence interval [95%CI]) to NG/CT treatment initiation and NG/CT-AE reporting were 0.20 (.16-.25) and 0.24 (.19-.27) at eThekwini versus 14.22 (14.12-15.09) and 15.12 (13.22-21.24) at Verulam/Isipingo (all P < .001). Median days (95%CI) to TV treatment initiation and TV-AE reporting were 0.17 (.12-.27) and 0.25 (.20-.99) at eThekwini versus 0.18 (.15-.2) and 0.24 (.15-.99) at Verulam/Isipingo (all P > .05). Cox regression analysis revealed that NG/CT treatment initiation (adjusted hazard ratio [aHR], 39.62 [95%CI, 15.13-103.74]) and NG/CT-AE reporting (aHR, 3.38 [95%CI, 2.23-5.13]) occurred faster at eThekwini versus Verulam/Isipingo, while times to TV treatment initiation (aHR, 0.93 [95%CI, .59-1.48]) and TV-AE reporting (aHR, 1.38 [95%CI, .86-2.21]) were similar. CONCLUSIONS: POC testing led to prompt STI management with potential therapeutic and prevention benefits, highlighting its utility as a diagnostic tool in resource-limited settings.

Burden of sexually transmitted infections from acute HIV infection among women in South Africa: Evidence from a prospective cohort study.

PURPOSE: HIV and other sexually transmitted infections (STIs) often co-occur. However, less evidence exists on the long-term STI dynamics among persons living with HIV in sub-Saharan Africa to inform interventions. We investigated the incidence, prevalence and factors associated with STIs, starting from acute HIV infection in a cohort of South African women. METHODS: The CAPRISA002 study enrolled women with acute HIV infection and performed STI testing and treatment 1-2 times annually from 2004-2020. We estimated STI incidence, re-infection, and prevalence trends before and after antiretroviral treatment (ART). We fitted Cox regression models to identify factors associated with STIs. RESULTS: We followed up 235 women (median age = 25 years, IQR 22-29) for 7.5 years (IQR 5.7-10.8). New STI and re-infection cases per 100 person-years (PYs) were 5.1 and 9.5 for Neisseria gonorrhoeae (NG), 7.4 and 14.7 for Chlamydia trachomatis (CT), 8.0 and 26.6 for Trichomonas vaginalis (TV), 7.7 and 16.7 for Mycoplasma genitalium (MG) and 25.2 and 37.3 for any STI. STI incidence, was associated with HIV log10 viral load (AHR = 1.24, 95% CI 1.06-1.44), active syphilis (AHR = 16.55, 95% CI 7.49-36.55), a positive HSV-2 PCR (AHR = 1.54, 95% CI 1.01-2.35), bacterial vaginosis (AHR = 1.48, 95% CI 1.01-2.18), recent regular sexual partners at enrolment (one vs none: AHR = 2.62, 95% CI 1.41-4.87; two plus vs none: AHR = 3.68, 95% CI 1.79-7.59) and age (5-year fold: AHR = 0.80, 95% CI 0.70-0.92). CONCLUSION: The persistent STI/HIV co-infection burden among South African women highlights that early HIV diagnosis and ART initiation needs to be combined with better STI care for women and their partners to prevent HIV and STI transmission.

Temporal Changes in Vaginal Microbiota and Genital Tract Cytokines Among South African Women Treated for Bacterial Vaginosis.

The standard treatment for bacterial vaginosis (BV) with oral metronidazole is often ineffective, and recurrence rates are high among African women. BV-associated anaerobes are closely associated with genital inflammation and HIV risk, which underscores the importance of understanding the interplay between vaginal microbiota and genital inflammation in response to treatment. In this cohort study, we therefore investigated the effects of metronidazole treatment on the vaginal microbiota and genital cytokines among symptomatic South African women with BV [defined as Nugent score (NS) ≥4] using 16S rRNA gene sequencing and multiplex bead arrays. Among 56 BV-positive women, we observed short-term BV clearance (NS <4) in a proportion of women six weeks after metronidazole treatment, with more than half of these experiencing recurrence by 12 weeks post-treatment. BV treatment temporarily reduced the relative abundance of BV-associated anaerobes (particularly Gardnerella vaginalis and Atopobium vaginae) and increased lactobacilli species (mainly L. iners), resulting in significantly altered mucosal immune milieu over time. In a linear mixed model, the median concentrations of pro-inflammatory cytokines and chemokines were significantly reduced in women who cleared BV compared to pre-treatment. BV persistence and recurrence were strongly associated with mucosal cytokine profiles that may increase the risk of HIV acquisition. Concentrations of these cytokines were differentially regulated by changes in the relative abundance of BVAB1 and G. vaginalis. We conclude that metronidazole for the treatment of BV induced short-term shifts in the vaginal microbiota and mucosal cytokines, while treatment failures promoted persistent elevation of pro-inflammatory cytokine concentrations in the genital tract. These data suggest the need to improve clinical management of BV to minimize BV related reproductive risk factors.

Recent Semen Exposure Impacts the Cytokine Response and Bacterial Vaginosis in Women.

Background: The presence of semen in the vagina from unprotected sex may influence the immune and microbial environment of the female genital tract. Inflammatory cytokine concentrations and BV-associated bacteria in female genital secretions may influence HIV risk, although the effect of recent sexual intercourse on incident BV and the cytokine milieu of cervicovaginal secretions has rarely been measured in previous studies. Here, we investigated the extent to which partner semen impacts the cytokine response and incident BV. Methods: At baseline, we assessed the recency of semen exposure in menstrual cup supernatants by quantifying prostate specific antigen (PSA) levels using ELISA in 248 HIV-uninfected women at high risk for HIV infection. Luminex was used to measure 48 cytokines in menstrual cup supernatants and vaginal swabs to diagnose BV by Nugent score. Point-of-care screening for Chlamydia trachomatis and Neisseria gonorrhoeae was conducted using GeneXpert while OSOM was used for Trichomonas vaginalis detection. Multivariable models, adjusted for age, sexually transmitted infections, BV, current contraception use and condom use, were used to assess the impact of semen exposure on biomarkers of inflammation and BV. Results: Presence of PSA, indicating recent semen exposure within 48 hours prior to sampling, was observed in menstrual cup supernatants of 17% (43/248) of women. Of these women, 70% (30/43) had self-reported condom use at their last sex act and 84% (36/43) had BV (Nugent score >7). PSA presence was significantly associated with prevalent BV (Relative Risk (RR), 2.609; 95% Confidence Interval (CI), 1.104 - 6.165; p = 0.029). Furthermore, women with detectable PSA had high median concentrations of macrophage inflammatory protein- beta (MIP-1α, p=0.047) and low median concentration of the stem cell growth factor beta (SCGF-ß, p=0.038) compared to those without PSA. Conclusion: A degree of discordance between self-reports of consistent condom use and PSA positivity was observed. There was also evidence of a relationship between recent semen exposure, BV prevalence and altered cytokine concentrations. These findings suggest that PSA, as a semen biomarker, should be taken into consideration when investigating biological markers in the female genital tract and self-reported condom use in studies on reproductive and sexual health.

HIV susceptibility in women: The roles of genital inflammation, sexually transmitted infections and the genital microbiome.

Given that heterosexual transmission of HIV across the genital mucosa is the most common route of infection in women, an in-depth understanding of the biological mechanisms associated with HIV risk in the female genital tract (FGT) is essential for effective control of the epidemic. Genital pro-inflammatory cytokines are well-described biological co-factors to HIV risk. Increased levels of pro-inflammatory cytokines in the FGT have been associated with a 3-fold higher-risk of acquiring HIV, presumably through involvement in barrier compromise and the recruitment of highly activated HIV target cells to the site of initial viral infection and replication. Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are suggested possible contributors to genital inflammation in the FGT, and this, coupled with the relationship between genital inflammation and HIV risk, underscores the importance of effective treatment of STI and BV in the promotion of women's health. In most low- and middle-income countries, STIs are treated syndromically, a practice providing rapid treatment without identifying the infection source. However, this approach has been associated with over-diagnosis and the overuse of drugs. Further, because many women with STIs are asymptomatic, syndromic management also fails to treat a vast proportion of infected women. Although several studies have explored the role of STIs and the vaginal microbiome on genital inflammation and HIV risk, the impact of STI and BV management on genital inflammation remains poorly understood. This review aimed to collate the evidence on how BV and STI management efforts affect genital inflammation and the genital microbiome in women.

Impact of point-of-care testing and treatment of sexually transmitted infections and bacterial vaginosis on genital tract inflammatory cytokines in a cohort of young South African women.

OBJECTIVES: STIs cause inflammation that is detrimental for both HIV risk and reproductive health. We assessed the impact of point-of-care (POC) STI testing, immediate treatment and expedited partner therapy (EPT) on genital tract cytokines among a cohort of young South African women. METHODS: HIV-negative women underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) by Xpert CT/NG and OSOM TV, and for bacterial vaginosis (BV) by microscopy. Women with STIs and/or BV received immediate treatment, EPT for STIs and retested after 6 and 12 weeks. Concentrations of 48 cytokines were measured in cervicovaginal fluid at each visit using multiplex ELISA technology. The impact of STI treatment on cytokine concentrations was assessed by multivariable linear mixed models and principal component analysis. RESULTS: The study enrolled 251 women with median age of 23 years (IQR 21-27). The prevalence of CT, NG and TV were 14.3%, 4.4% and 4.0%, and 34.3% had BV. Women with STIs or BV at baseline (n=94) had significantly higher concentrations of pro-inflammatory cytokines (interleukin (IL)-1α, IL-1ß, IL-6, tumour necrosis factor (TNF)-α, TNF-ß, IL-18 and macrophage inflammatory factor (MIF)) and chemokines (IL-8, IL-16, macrophage inflammatory protein (MIP)-1α, IFN-α2, monokine induced by gamma interferon (MIG), monocyte chemoattractant protein (MCP)-3, regulated on activation normal T cell expressed and secreted and eotaxin) compared with women without (n=157). STI treatment was strongly associated with reduced concentrations of pro-inflammatory cytokines IL-6 (p=0.004), IL-1ß (p=0.013), TNF-α (p=0.018) and chemokines MIG (p=0.008) and growth-related oncogene (GRO)-α (p=0.025). A lower Nugent score was associated with a reduction in pro-inflammatory cytokines IL-1α (p=0.003), TNF-related apoptosis-inducing ligand (p=0.004), MIF (p=0.010) and IL-18 (p<0.001), but an increase in chemokines MIG (p=0.020), GRO-α (p<0.001), IP-10 (p<0.001), MIP-1ß (p=0.008) and MCP-1 (p=0.005). Principal component analysis showed differences in STI and BV-related inflammatory profiles, but that resolution restored a profile consistent with vaginal health. CONCLUSIONS: A comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk.

Genital HSV-1 DNA detection is associated with a low inflammatory profile in HIV-uninfected South African women.

OBJECTIVES: Genital herpes simplex virus (HSV) infections are common in South Africa and worldwide. While HSV-2 is known to cause genital lesions, HSV-1 is better known to cause oral infections. Due to the global rise in genital HSV-1 infections, we aimed to compare the genital cytokine environment associated with HSV-1 and HSV-2 infections and their relation to the proinflammatory genital immune environment associated with HIV risk in African women. METHODS: HSV-1 and HSV-2 DNA were detected by quantitative real-time PCR in menstrual cup specimens collected from 251 HIV-negative women participating in the CAPRISA 083 study in Durban, South Africa. HSV shedding was defined as detection at >150 copies/mL. Forty-eight cytokines were measured in genital fluid by multiplexed ELISA, and multivariable regression models determined associations between genital cytokines and HSV DNA detection. RESULTS: HSV-1 DNA detection (24/251 (9.6%)) and shedding (13/24 (54.2%)) was more common than HSV-2 (detection in 14/251 (5.6%), shedding in 0/14). None of the women with detectable HSV had evidence of genital lesions. HSV-2 DNA detection was associated with increased interleukin (IL)-18 and decreased cutaneous T-cell attracting chemokine concentrations, but only in univariable analysis. By contrast, in both univariable and multivariable analyses, the detection of HSV-1 DNA was associated with reduced concentrations of granulocyte-colony stimulating factor, IL-7, IL-4, platelet-derived growth factor-ßß and five proinflammatory cytokines associated with HIV risk: IL-6, IL-1ß, macrophage inflammatory protein (MIP)-1α, MIP-1ß and tumour necrosis factor-α. CONCLUSIONS: That HSV-1 DNA was more commonly detected and shed than HSV-2 emphasises the need for clinical screening of both viruses, not just HSV-2 in young women. Efforts to reduce genital inflammation may need to consider implementing additional strategies to mitigate a rise in HSV replication.

Sex and Male Circumcision: Women's Preferences Across Different Cultures and Countries: A Systematic Review.

INTRODUCTION: Women's choices for a sexual partner are influenced by numerous personal, cultural, social, political and religious factors, and may also include aspects of penile anatomy such as male circumcision (MC) status. AIM: To perform a systematic review examining (i) whether MC status influences women's preference for sexual activity and the reasons for this, and (ii) whether women prefer MC for their sons. METHODS: PRISMA-compliant searches were conducted of PubMed, Google Scholar, Embase, and the Cochrane Database of Systematic Reviews. Articles that met the inclusion criteria were rated for quality using the SIGN system. RESULTS: Database searches identified 29 publications with original data for inclusion, including 22 for aim (i) and 4 of these and 7 others pertaining to aim (ii). In the overwhelming majority of studies, women expressed a preference for the circumcised penis. The main reasons given for this preference were better appearance, better hygiene, reduced risk of infection, and enhanced sexual activity, including vaginal intercourse, manual stimulation, and fellatio. In studies that assessed mothers' preference for MC of sons, health, disease prevention, and hygiene were cited as major reasons for this preference. Cultural differences in preference were evident among some of the studies examined. Nevertheless, a preference for a circumcised penis was seen in most populations regardless of the frequency of MC in the study setting. CONCLUSION: Women's preferences generally favor the circumcised penis for sexual activity, hygiene, and lower risk of infection. The findings add to the already well-established health benefits favoring MC and provide important sociosexual information on an issue of widespread interest. Morris BJ, Hankins CA, Lumbers ER, et al. Sex and Male Circumcision: Women's Preferences Across Different Cultures and Countries: A Systematic Review. Sex Med 2019;7:145-161.

Diagnostic accuracy of the Xpert CT/NG and OSOM Trichomonas Rapid assays for point-of-care STI testing among young women in South Africa: a cross-sectional study.

OBJECTIVES: Syndromic management of sexually transmitted infections (STIs) omits asymptomatic infections, particularly among women. Accurate point-of-care assays may improve STI care in low- and middle-income countries (LMICs). We aimed to evaluate the diagnostic performance of the Xpert Chlamydia trachomatis/Neisseria gonorrhoeae (CT/NG) and OSOM Trichomonas vaginalis (TV) Test as part of a STI care model for young women in South Africa. DESIGN: Diagnostic evaluation conducted as part of a prospective cohort study (CAPRISA 083) between May 2016 and January 2017. SETTING: One large public healthcare facility in central Durban, KwaZulu-Natal, South Africa PARTICIPANTS: 247 women, aged 18-40 years, attending for sexual and reproductive services to the clinic. Pregnant and HIV-positive women were excluded. OUTCOMES: Diagnostic performance of the Xpert CT/NG and OSOM TV assays against the laboratory-based Anyplex II STI-7 Detection. All discordant results were further tested on the Fast Track Diagnostics (FTD) STD9 assay. RESULTS: We obtained vaginal swabs from 247 women and found 96.8% (239/247) concordance between Xpert and Anyplex for CT and 100% (247/247) for NG. All eight discrepant CT results were positive on Xpert, but negative on Anyplex. FTD STD9 confirmed three positive and five negative results, giving a confirmed prevalence of CT 15.0% (95% CI 10.5 to 19.4), NG 4.9% (2.2-7.5) and TV 3.2% (1.0-5.4). Sensitivity and specificity of Xpert CT/NG were 100% (100-100) and 97.6% (95.6-99.7) for CT and 100% (100-100) and 100% (100-100) for NG. The sensitivity and specificity of OSOM TV were 75.0% (45.0-100) and 100% (100-100). CONCLUSION: The Xpert CT/NG showed high accuracy among young South African women and combined with the OSOM TV proved a useful tool in this high HIV/STI burden setting. Further implementation and cost-effectiveness studies are needed to assess the potential role of this assay for diagnostic STI testing in LMICs. TRIAL REGISTRATION NUMBER: NCT03407586; Pre-results.

Does Male Circumcision Reduce Women's Risk of Sexually Transmitted Infections, Cervical Cancer, and Associated Conditions?

Background: Male circumcision (MC) is proven to substantially reduce men's risk of a number of sexually transmitted infections (STIs). We conducted a detailed systematic review of the scientific literature to determine the relationship between MC and risk of STIs and associated conditions in women. Methods: Database searches by "circumcision women" and "circumcision female" identified 68 relevant articles for inclusion. Examination of bibliographies of these yielded 14 further publications. Each was rated for quality using a conventional rating system. Results: Evaluation of the data from the studies retrieved showed that MC is associated with a reduced risk in women of being infected by oncogenic human papillomavirus (HPV) genotypes and of contracting cervical cancer. Data from randomized controlled trials and other studies has confirmed that partner MC reduces women's risk not only of oncogenic HPV, but as well Trichomonas vaginalis, bacterial vaginosis and possibly genital ulcer disease. For herpes simplex virus type 2, Chlamydia trachomatis, Treponema pallidum, human immunodeficiency virus and candidiasis, the evidence is mixed. Male partner MC did not reduce risk of gonorrhea, Mycoplasma genitalium, dysuria or vaginal discharge in women. Conclusion: MC reduces risk of oncogenic HPV genotypes, cervical cancer, T. vaginalis, bacterial vaginosis and possibly genital ulcer disease in women. The reduction in risk of these STIs and cervical cancer adds to the data supporting global efforts to deploy MC as a health-promoting and life-saving public health measure and supplements other STI prevention strategies.

Beyond syndromic management: Opportunities for diagnosis-based treatment of sexually transmitted infections in low- and middle-income countries.

INTRODUCTION: In light of the limited impact the syndromic management approach has had on the global sexually transmitted infection (STI) epidemic, we assessed a care model comprising point-of-care (POC) STI testing, immediate treatment, and expedited partner therapy (EPT) among a cohort of young women at high HIV risk in South Africa. METHODS AND FINDINGS: HIV negative women presenting for STI care underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV), and swabs were sent for NG culture and susceptibility testing. Results were available within 2 hours and women with STIs were immediately treated and offered EPT packs, including medication, condoms, and information for sexual partners. An EPT questionnaire was administered after one week, and women retested for STIs after 6 and 12 weeks. 267 women, median age 23 (IQR 21-26), were recruited and 88.4% (236/267) reported genital symptoms. STI prevalence was CT 18.4% (95%CI 13.7-23.0), NG 5.2% (95%CI 2.6-7.9) and TV 3.0% (95%CI 1.0-5.0). After 12 weeks, all but one NG and two CT infections were cleared. No cephalosporin-resistant NG was detected. Of 63/267 women (23.6%) diagnosed with STIs, 98.4% (62/63) were offered and 87.1% (54/62) accepted EPT. At one week 88.9% (48/54) stated that their partner had taken the medication. No allergic reactions or social harms were reported. Of 51 women completing 6-week follow up, detection rates were lower amongst women receiving EPT (2.2%, 1/46) compared to those who did not (40.0%, 2/5), p = 0.023. During focus group discussions women supported the care model, because they received a rapid, specific diagnosis, and could facilitate their partners' treatment. CONCLUSIONS: POC STI testing and EPT were acceptable to young South African women and their partners, and could play an important role in reducing STI reinfection rates and HIV risk. Larger studies should evaluate the feasibility and cost-effectiveness of implementing this strategy at population level.

Early infant male circumcision: Systematic review, risk-benefit analysis, and progress in policy.

AIM: To determine whether recent evidence-based United States policies on male circumcision (MC) apply to comparable Anglophone countries, Australia and New Zealand. METHODS: Articles in 2005 through 2015 were retrieved from PubMed using the keyword "circumcision" together with 36 relevant subtopics. A further PubMed search was performed for articles published in 2016. Searches of the EMBASE and Cochrane databases did not yield additional citable articles. Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further. The most relevant and representative of the topic were included. Bibliographies were examined to retrieve further key references. Randomized controlled trials, recent high quality systematic reviews or meta-analyses (level 1++ or 1+ evidence) were prioritized for inclusion. A risk-benefit analysis of articles rated for quality was performed. For efficiency and reliability, recent randomized controlled trials, meta-analyses, high quality systematic reviews and large well-designed studies were used if available. Internet searches were conducted for other relevant information, including policies and Australian data on claims under Medicare for MC. RESULTS: Evidence-based policy statements by the American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) support infant and later age male circumcision (MC) as a desirable public health measure. Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria. Together, these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects, phimosis that causes difficult and painful erections and "ballooning" during urination, inflammatory skin conditions, inferior penile hygiene, candidiasis, various sexually transmissible infections in both sexes, genital ulcers, and penile, prostate and cervical cancer. Our risk-benefit analysis showed that benefits exceeded procedural risks, which are predominantly minor, by up to 200 to 1. We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime. Wide-ranging evidence from surveys, physiological measurements, and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function, sensitivity or pleasure. United States studies showed that early infant MC is cost saving. The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews. CONCLUSION: Affirmative MC policies are needed in Australia and New Zealand. Routine provision of accurate, unbiased education, and access in public hospitals, will maximize health and financial benefits.

Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection.

BACKGROUND: Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. METHODS: We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. RESULTS: The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005). CONCLUSIONS: In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.).

Efficacy of human papillomavirus 16 and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and precancer in young women: final event-driven analysis of the randomized, double-blind PATRICIA trial.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.).